Therapeutic Potential of Dopamine and Related Drugs as Anti-Inflammatories and Antioxidants in Neuronal and Non-Neuronal Pathologies

Dopamine (DA), its derivatives, and dopaminergic drugs are compounds widely used in the management of diseases related to the nervous system. However, DA receptors have been identified in nonneuronal tissues, which has been related to their therapeutic potential in pathologies such as sepsis or septic shock, blood pressure, renal failure, diabetes, and obesity, among others. In addition, DA and dopaminergic drugs have shown anti-inflammatory and antioxidant properties in different kinds of cells. Aim: To compile the mechanism of action of DA and the main dopaminergic drugs and show the findings that support the therapeutic potential of these molecules for the treatment of neurological and non-neurological diseases considering their antioxidant and anti-inflammatory actions. Method: We performed a review article. An exhaustive search for information was carried out in specialized databases such as PubMed, PubChem, ProQuest, EBSCO, Scopus, Science Direct, Web of Science, Bookshelf, DrugBank, Livertox, and Clinical Trials. Results: We showed that DA and dopaminergic drugs have emerged for the management of neuronal and nonneuronal diseases with important therapeutic potential as anti-inflammatories and antioxidants. Conclusions: DA and DA derivatives can be an attractive treatment strategy and a promising approach to slowing the progression of disorders through repositioning.


Introduction
Dopamine (DA) is a monoamine synthesized mainly in neurons of the midbrain cores, ventral tegmental area, and substantia nigra pars compacta. The synthesis of the neurotransmitter takes place in the dopaminergic nerves [1]. Hydroxylation of the amino acid L-tyrosine is the point of regulation of the synthesis of catecholamines, including DA, in the central nervous system (CNS), and consequently, the tyrosine hydroxylase (TH) enzyme Figure 1. Synthesis, release, catabolism, and postsynaptic action of dopamine. Synthesis: The TH enzyme converts L-tyrosine to L-DOPA; then, the AADC enzyme allows the production of dopamine, which is loaded into synaptic vesicles by VMAT-2. Release and recycling: once released in the synaptic cleft, the DAT transporter reuptakes dopamine, which is recycled into synaptic vesicles. Catabolism: Dopamine is degraded by specialized enzymes; the MAO enzyme breaks down dopamine to DOPAC and DOPET. In the synaptic cleft, the COMT enzyme catalyzes dopamine to HVA, which is the main end-product of dopamine degradation. At the post-synapse, dopamine binds with D1-like and D2-like receptors. The D1-like receptor activates the Gαs/olf subunit, which stimulates Figure 1. Synthesis, release, catabolism, and postsynaptic action of dopamine. Synthesis: The TH enzyme converts L-tyrosine to L-DOPA; then, the AADC enzyme allows the production of dopamine, which is loaded into synaptic vesicles by VMAT-2. Release and recycling: once released in the synaptic cleft, the DAT transporter reuptakes dopamine, which is recycled into synaptic vesicles. Catabolism: Dopamine is degraded by specialized enzymes; the MAO enzyme breaks down dopamine to DOPAC and DOPET. In the synaptic cleft, the COMT enzyme catalyzes dopamine to HVA, which is the main end-product of dopamine degradation. At the post-synapse, dopamine binds with D1-like and D2-like receptors. The D1-like receptor activates the G αs/olf subunit, which stimulates adenylyl cyclase protein, increasing protein phosphorylation. D2-like receptor, by activating the G αi/o subunit, inhibits the protein adenylyl cyclase, generating a decrease in protein phosphorylation.

Chemical Compounds and Drugs Related to the Dopaminergic System
There are more than 200 chemical compounds and drugs related to the dopaminergic system [27][28][29], and mentioning each of them is beyond the scope of this work; however, they can be grouped, according to their activity, as precursors [30][31][32][33], agonists and antagonists of receptors [34], DA reuptake inhibitors [35,36] DA releasing agents [36,37], activity enhancers [38][39][40], and enzyme inhibitors [41], among others. Three DA precursors are used in the clinic, L-phenylalanine, L-tyrosine, and L-DOPA; tyrosine is a nonessential amino acid that is synthesized from the essential aromatic amino acid phenylalanine, and both amino acids constitute the two initial steps in the biosynthesis of DA [31]. Levodopa (L-DOPA) is a dopamine precursor and is the most effective and commonly used drug for the treatment of Parkinson's disease. Levodopa is prescribed in most cases with Carbidopa, which is an inhibitor of L-amino acid decarboxylase, the enzyme that metabolizes levodopa peripherally [42].
DA agonists exert their effects by acting directly on dopamine receptors and mimicking endogenous neurotransmitters. There are two subclasses, ergoline, and nonergoline agonists, with a variable affinity for different DA receptors [43,44]. DA antagonists block the effects of dopamine or its agonists by binding to DA receptors. A variety of DA antagonists are used for the treatment of psychotic disorders; however, their therapeutic effects are mostly due to long-term adjustments rather than acute blockade of DA receptors [29]. Some DA antagonists have been used to treat Tourette's syndrome or hiccups [45,46], and they have also been used as antiemetics to treat various causes of nausea and vomiting [47]. Table 1 details the mechanisms of action and indications of DA precursors and the most representative dopaminergic agonist and antagonist drugs.
On the other hand, DA reuptake inhibitors may be classified as DAT inhibitors and VMAT inhibitors. The former block the action of DAT, and DA reuptake inhibition occurs when extracellular DA, which does not bind to the postsynaptic neuron, is blocked from re-entering the presynaptic neuron, resulting in increased extracellular concentrations of DA and an increase in dopaminergic neurotransmission [80]. DAT inhibitors are indicated for the treatment of attention deficit hyperactivity disorder, major depressive disorder, and seasonal affective disorder and as an aid to smoking cessation; examples are methylphenidate [27,29]. On the other hand, VMAT inhibitors prevent the reuptake and storage of monoamine neurotransmitters in synaptic vesicles, making them vulnerable to metabolism by cytosolic enzymes. Inhibition of VMAT-2 results in decreased reuptake of monoamines and depletion of their reserves in nerve terminals. They are used to treat chorea due to neurodegenerative diseases or dyskinesias due to neuroleptic medications; examples are tetrabenazine, deutetrabenazine, and valbenazine [27,42,[81][82][83].
DA enzyme inhibitors can be classified into DA synthesis inhibitors and DA degradation inhibitors. There are three kinds of dopamine synthesis inhibitors: (1) TH inhibitors (for example, 3-iodo-tyrosine and metyrosine), which are able to inhibit TH activity, the rate-limiting enzyme in DA biosynthesis [90]; (2) phenylalanine hydroxylase inhibitors (for example, 3,4-dihydroxystyrene), which inhibit the enzyme that converts phenylalanine to tyrosine [91]; and (3) DOPA decarboxylase inhibitors, which block the biosynthesis of L-DOPA to DA. Examples of these inhibitors are benserazide and carbidopa, commonly used in combination with levodopa. Since they can hardly cross the blood-brain barrier, they prevent the formation of dopamine in extracerebral tissues, minimizing the occurrence of extracerebral side effects [92,93]. Table 1. Mechanism of action and indications of dopamine precursors and dopaminergic agonist and antagonist drugs.

SCH23390
Highly potent and selective of D1 dopamine receptor Scientific research of drug addiction [79] Finally, the main DA degradation inhibitors can be classified into MAO and COMT inhibitors. The most prescribed MAO inhibitors are selegiline, isocarboxazid, phenelzine, and tranylcypromine. They have in common the ability to block oxidative deamination of DA and subsequently provoke its elevation in brain levels, enhancing dopaminergic activity [29,94]. Selegiline is close structurally to (-) methamphetamine and is a selective and irreversible inhibitor of monoamine oxidase type B (MAO-B). Selegiline is the first catecholaminergic activity-enhancing substance in clinical use that does not continually release catecholamines and is, therefore, free of amphetamine dependence [38,40]. Likewise, the most common COMT inhibitors are entacapone, opicapone, and tolcapone. They inhibit the COMT enzyme and are frequently used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa medication [95][96][97]. Many Parkinson's disease patients treated with levodopa plus carbidopa experience motor complications over time; when COMT inhibitors are administered, plasma levodopa levels are increased and maintained, resulting in more consistent dopaminergic stimulation, leading to further reduction of the manifestations of parkinsonian syndrome [98].
In summary, dopaminergic compounds and drugs act through a variety of mechanisms of action within the process of synthesis, release, catabolism, and postsynaptic action of dopamine, as shown in Figure 2. It should be noted that these main mechanisms are often accompanied by secondary mechanisms (such as antioxidant or anti-inflammatory mechanisms, see below, which are not yet fully understood) that give a wide variety of effects and indications as potential adjuvants in most chronic and degenerative diseases. In summary, dopaminergic compounds and drugs act through a variety of mechanisms of action within the process of synthesis, release, catabolism, and postsynaptic action of dopamine, as shown in Figure 2. It should be noted that these main mechanisms are often accompanied by secondary mechanisms (such as antioxidant or anti-inflammatory mechanisms, see below, which are not yet fully understood) that give a wide variety of effects and indications as potential adjuvants in most chronic and degenerative diseases. Figure 2. Mechanism of action of chemical compounds and drugs related to the dopaminergic system. These drugs can inhibit or activate diverse proteins involved in dopamine metabolism, including precursors, enzyme inhibitors, dopamine-releasing agents, dopamine reuptake inhibitors, dopamine activity enhancers, and agonists or antagonists of D1-like and D2-like receptors. At presynapses: The precursors enable the biosynthesis of dopamine. VMAT inhibitors prevent the storage of monoamines in synaptic vesicles, resulting in the depletion of these neurotransmitters. DAT inhibitors keep dopamine in the synaptic cleft longer by inhibiting its reuptake. Dopamine-releasing agents and dopamine activity enhancers increase the release of the activity of dopamine into the synaptic cleft. Dopamine synthesis inhibitors prevent the formation of dopamine as an endpoint. Dopamine degradation inhibitors enhance dopaminergic activity by blocking dopamine catabolism. At postsynapses: The dopamine agonist (orange box) mimics endogenous dopamine function, thus activating or inhibiting adenylyl cyclase depending on whether it binds to D1-like or D2-like receptors, respectively. Dopamine antagonists (pink box) bind to but do not activate dopamine receptors, thereby blocking the actions of dopamine. L-Phe: L-phenylalanine, L-Tyr: L-tyrosine, TH: tyrosine

Antioxidant and Anti-Inflammatory Properties of Dopamine and Related Drugs
In 1997, it was reported for the first time that DA has a direct antioxidant effect due to the number of hydroxy groups on the phenolic ring of the molecule. In this sense, Yen and Hsieh [99] showed that DA has a protective effect against the oxidation of linoleic acid, has reducing power, and shows scavenger capacity against 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radicals, superoxide radicals (O 2 •− ) and hydroxyl radicals (HO•) ( tion hydroxy group on the phenolic ring and the side chain is an electron-donating amine group [99]. Later, it was shown that DA and D4 receptors induced nuclear factor-erythroid 2 related factor 2 (Nrf2) activity during ischemia in vivo in astrocyte and meningeal cell cultures, showing its capacity to modulate the antioxidant effect; Nrf2 is a transcription factor that controls inducible expression of multiple antioxidant/detoxification genes [100,101] and induces the expression of heme oxygenase-1 (HO-1) by human endothelial cells in vitro [102]. The anti-inflammatory effect of DA has also been demonstrated in alcoholic hemorrhagic pancreatitis in cats [103]. In fact, DA has been proposed as an immune transmitter, given that dopaminergic signaling is involved in neurological diseases and is associated with the inflammatory response [104]. DA inhibits cytokine production via D1 receptors, decreases oxidative stress [105], and can cause nuclear factor kappa B (NF-kB), a transcription factor that mediates the control of ROS and inhibition in acute kidney injury [106]. Catecholamines, including DA, can inhibit tumor necrosis factor-alpha (TNFα) and may enhance interleukin-6 (IL-6) and interleukin-10 (IL-10) production through D2, D3, or D1/D5 receptors [107][108][109]. In fact, DA has been proposed to be a putative anti-inflammatory cytokine by itself attenuating the chemoattractant effect of interleukin-8 (IL-8), integrins CD11b and CD18, and the adhesion molecules E-selectin and intercellular adhesion molecule 1 (ICAM-1) [110]. DA and its D1 receptor also inhibit the activation of the protein complex named NLR family pyrin domain containing 3 (NLRP3) inflammasome in bone marrow-derived macrophages [111,112]. On the other hand, it has been shown that catechol moieties protect cells against oxidative damage and downregulate the proinflammatory cytokine interleukine-1beta (IL-1β) in human bone marrow mesenchymal stem cells [113]. Catecholamines identified in two medicinal plants (Santolina chamaecyparissus and Launaea mucronate) have also shown antioxidant and anti-inflammatory effects in carrageenan-induced paw edema in a rat model [114]. DA also inhibited the peroxidation of brain phospholipids and reaction with radicals such as trichloromethyl peroxyl radicals (CCl 3 O 2 •), O 2 •− , peroxynitrite (ONOO − ) and hydrochlorous acid (HOCl) generated in vitro [115][116][117]. Moreover, the antioxidant effect of DA derivatives of several plant species, such as soybean, avocado, apple, cucumber, and banana, has also been reported, showing an increase in antioxidant enzyme activities (superoxide dismutase, SOD; catalase, CAT; glutathione reductase, GR) and reactive oxygen species (hydrogen peroxide, H 2 O 2 , nitric oxide, NO•, and O 2 •− ) scavenging capacity [118][119][120][121][122][123]. In another work, it was shown that other derivatives of DA-related compounds or DA agonists showed antioxidant activity. It has been shown that phenolic sulfonamides showed scavenger capacity in vitro against DPPH, 2,2 -azinobis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS), and O 2 •− [124]. N-Nicotinoyl dopamine also showed antioxidant properties with DPPH scavenging activity and protected against ROS accumulation induced by UVB irradiation in HaCat cells [125]. Bromocriptine, a DA agonist, scavenged O 2 •− , 5,5-dimethyl-1-pyrroline-N-oxide hydroxide, and DPPH radicals generated through in vitro systems [9]. This compound also activates NAD(P)H quinone oxidoreductase 1 (NQO1) via Nrf2-phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling in H 2 O 2 -treated PC12 cells, protecting against oxidative damage [126]. In in vivo experimental work, it was shown that a non-ergot DA agonist named ropinirole showed a neuroprotective effect, increased GSH, CAT, and SOD antioxidant activities in the striatum, protected striatal dopaminergic neurons against 6-hydroxydopamine (6-OHDA) in mice [14] and was an activator of the GHS system in the mouse striatum [127]. Pramipexole, a DA agonist, protects the DAergic cell line MES 23.5 against 6-OHDA and H 2 O 2, increasing cellular levels of GSH, glutathione peroxidase (GPx), and CAT activities [11,12] and scavenging HO• induced by 6-OHDA in rats [13]. In an in vivo model using [3H] pramipexole, it has been shown that the drug enters and accumulates in cells and mitochondria. Pramipexole also prolongs survival time in SOD-1-G93A mice, a model of familial amyotrophic lateral sclerosis [128]. Cabergoline, an ergot derivative DA agonist, has the ability to activate GSH, CAT, and SOD against the neurotoxicity of 6-OHDA in mice, reducing lipid peroxidation [10] and showing antioxidant activity against oxidation in phosphatidylcholine liposomes [129]. D-390, a novel D2/D3 receptor agonist, also showed potent iron chelation [130], and a new tris (DA) derivative also showed Fe(III), Mg(II), Zn(II), and Fe(II) chelation and antioxidant activity in neuron-like rat pheochromocytoma cells [131]. Other DA derivatives, such as N-arachidonoyl-DA and apomorphine, and DA-related compounds, such as pukateine [(R)-11-hydroxy-1,2-methylenedioxyaporphine], have also shown antioxidant properties [60,[132][133][134]. It has been shown that caffeic acid anilides and caffeic acid dopamine amide showed DPPH scavenging capacity and microsomal lipid peroxidation-inhibiting activity [135]. Recently, the water-soluble caffeic acid-DA hydrochloride complex has been proposed as a bactericidal, antibiofilm, and antitumoral agent in the physiological pH range (5.5-7.5) due to its antioxidant properties [136].
Recent clinical research findings indicate that melatonin may modulate dopaminergic pathways involved in movement disorders in humans. It has been proposed that the interaction of melatonin with the dopaminergic system may play a significant role in the nonphotic and photic entrainment of the biological clock as well as in the fine-tuning of motor coordination in the striatum principally because these interactions, by its antioxidant nature can be beneficial in humans [137][138][139]. Additionally, its anti-inflammatory properties have been proposed for the treatment of inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis [140,141]. In relation to pathologies not related to the central nervous system, the use of DA-melanin nanoparticles has been proposed as a novel scavenger of ROS and reactive nitrogen species (RNS). These nanoparticles showed low cytotoxicity and a strong ability to scavenge ROS and RNS: O 2 •− , HO• radicals, and ONOO − were proposed as potent anti-inflammatory and chondroprotective agents due to their average diameter of 112.5 nm. Nanoparticles can be intra-articularly injected into an affected joint and retained at the injection site, as was shown in an osteoarthritis rodent model and in chondrocyte cultures. These nanoparticles also diminished IL-1β and reduced proteoglycan loss, probably stimulating autophagy for chondrocyte protection. IL-1β caused an increase in the gene expression of autophagy markers: protein 1A/1B-light chain 3 (LC3-11), autophagy-related 7 (ATG7), and beclin-1 [142]. The use of N-acyl dopamine derivates has also been proposed as a potential alternative for implementation in transplantation medicine due to its immunomodulatory, cytoprotective, and anti-inflammatory properties [143]. The antioxidant and anti-inflammatory properties of DA and some related drugs are summarized in Figure 3.
Finally, it is important to mention that in cancer, DA agonists inhibit T-cell proliferation and cytotoxicity, probably through activation of the D1 receptor, which promotes an increase in intracellular cAMP, contributing to immune regulation [144]. Additionally, these agonists have an important role due to their beneficial antiangiogenic effects. Hoeppner et al., 2015 [145] showed that D2 receptor agonists inhibit NADPH oxidase activity, reducing the production of ROS involved in angiogenesis [145]. Leng et al., 2017 [146] found in GH3 cells that D5 receptor agonists could inhibit the activity and expression of SOD-1 and increase ROS, promoting autophagy and cell death by inhibiting the AKT-mammalian target of rapamycin (mTOR) pathway [146].

Clinical Trials in Nonneuronal Pathologies
DA, agonists, or derivatives are being tested as possible drugs or adjuvants in other non-CNS pathologies, possibly due to their antioxidant or anti-inflammatory/immunomodulatory properties. In this sense, DA, serotonin, prostaglandin E2, substance P, and lipoperoxidation levels are decreased, whereas SOD levels are increased after pain treatment with warm acupuncture and meloxicam in patients with knee osteoarthritis, showing the involvement of these biochemical markers as anti-inflammatory mediators [147]. DA treatment (15 μg/kg/min) is also effective in increasing blood pressure in neonates with hypothermia treatment for hypoxic-ischemic encephalopathy [148], and the use of the DA synthetic analog dopexamine in doses of 0.5 and 2.0 μg/kg/min significantly protected the upper gastrointestinal mucosa in the of patients with abdominal surgery, reducing the incidence of acute inflammation and decreasing myeloperoxidase activity and inducible nitric oxide synthase in biopsies [149]. The effects of DA (2.5 to 10 μg/kg/min)

Clinical Trials in Nonneuronal Pathologies
DA, agonists, or derivatives are being tested as possible drugs or adjuvants in other non-CNS pathologies, possibly due to their antioxidant or anti-inflammatory/immunomodulatory properties. In this sense, DA, serotonin, prostaglandin E2, substance P, and lipoperoxidation levels are decreased, whereas SOD levels are increased after pain treatment with warm acupuncture and meloxicam in patients with knee osteoarthritis, showing the involvement of these biochemical markers as anti-inflammatory mediators [147]. DA treatment (15 µg/kg/min) is also effective in increasing blood pressure in neonates with hypothermia treatment for hypoxic-ischemic encephalopathy [148], and the use of the DA synthetic analog dopexamine in doses of 0.5 and 2.0 µg/kg/min significantly protected the upper gastrointestinal mucosa in the of patients with abdominal surgery, reducing the incidence of acute inflammation and decreasing myeloperoxidase activity and inducible nitric oxide synthase in biopsies [149]. The effects of DA (2.5 to 10 µg/kg/min) have also been observed in patients with sepsis, where its administration was associated with a fall in lactate and no effect on arterial pH [150]. DA (10 to 25 µg/kg/min) is effective in the treatment of patients with hyperdynamic septic shock, where it successfully improved the systemic vascular resistance index, cardiac index, oxygen delivery and uptake [151]. It has been shown that DA (infused at 2 and 4 µg/kg/min) increases renal oxygenation with no increase in tubular sodium reabsorption or renal oxygen consumption in glomerular filtration rate in postcardiac surgery patients [152]. Bromocriptine has also been proposed as an adjuvant in immunosuppression after renal transplantation, but its effectiveness has not yet been widely shown [153,154]. Additionally, bromocriptine (2.5 mg twice daily) prevented ulcer relapse for six months in patients with duodenal ulcers [155]. The use of pramipexole (from 0.25 to 0.75 mg) has shown efficacy in the treatment of restless legs syndrome in patients [156,157]. The use of cabergoline (0.5 mg for eight days) and bromocriptine (2.5 mg for 16 days) are efficient in the prevention of moderate and early-onset ovarian hyperstimulation syndrome in patients [158]. The role of DA in crucial social role decision-making was shown using pramipexole in women, allowing them to become less generous in general, modulate smoking behavior or produce subjective effects of cocaine, improve sleep behavior disorder and tinnitus, and help against pain, fatigue, function, and global status in patients with fibromyalgia [159][160][161][162][163][164][165]. Finally, Table 2 summarizes diverse clinical trials in progress.  Gastric diseases

Discussion and Conclusions
This is an important work in which the applications of DA and its derivatives are reviewed, offering physicians and healthcare personnel information that may be valuable to make therapeutic decisions considering the advances in the field of knowledge of the use of drugs (of natural or synthetic origin) and/or their action targets. In the present work, we showed that DA and dopaminergic drugs have emerged for the management of diseases, mainly at the neuronal level; however, they have been proposed for the treatment of pathologies that are not directly related to the nervous system, possibly due to their anti-inflammatory and antioxidant properties. Cabergoline, fenoldopam, bromocriptine, domperidone, pramipexole, rotigotine, and quinagolide, among others, are being tested for sepsis or septic shock, renal failure, gastric diseases, cancer, brain trauma injury, blood pressure, and fibromyalgia. DA receptor agonists or antagonists can function through classical G protein signaling regulating AKT/NF-κB, rat sarcoma virus (Ras)/PI3K/AKT, cAMPresponse element binding protein (CREB)/NF-κB or signal transducers and activators of transcription (STAT) pathways inhibiting or activating nuclear transcription or downstream related factors such as NRLP3 inflammasome expression, mTOR, Nrf2 or a tool-like receptor (TLR). Additionally, they can function through other nonreceptor-dependent pathways as L-type Ca 2+ channels. However, DA and related drugs should be further studied to more precisely understand the molecular and biochemical mechanisms underlying the large number of therapeutic effects considered in this review. Moreover, because DA receptors have multiple physiological roles in neurological and systemic diseases, more preclinical studies are necessary to elucidate the specific functions of DA receptor subtypes.
On the other hand, considering that many systemic and neurodegenerative diseases are characterized by the presence of inflammation, related in turn to oxidative stress, DA and DA derivatives can be an attractive option as a strategy of treatment and a promising approach to slowing the progression of disorders through the repositioning of DA. In this sense, our review is important since we mention the possible mechanisms by which DA and its derivatives act as anti-inflammatory and antioxidant compounds in in-vitro studies, animal models, and clinical trials where their therapeutic application is being tested.
Furthermore, it is necessary to study natural products containing DA. In this review, some products, such as fruits, vegetables, and plants with dopaminergic content, have shown antioxidant or anti-inflammatory properties. In the literature, active metabolites such as stepholidine (in Chinese herb), pukatein (natural aporphine derivative), salsolinol (in bananas), hordenine (a constituent of barley and beer), goitrin (in brassicaceous weeds), bromophenols curcumin or cannabinoids that showed dopaminergic properties due to the interaction with DA receptors modulating its signaling are also being considered as possible therapeutic agents. In relation to products of natural origin, first, experimental studies are necessary to understand the dynamic behavior of DA receptors and their interaction modes with active metabolites to understand the relevant structural and functional characteristics of these receptors for interaction with metabolites that function as agonists, antagonists or blockers. Second, more experimental and clinical studies are needed to establish which products of natural origin can be used for the treatment of non-neurological diseases related to DA metabolism.